Substituted thiopyrano(2,3-c)pyrazoles

ABSTRACT

1,3-DISUBSTITUTED-5,6-DIHYDROTHIOPYRANO(2,3-C) PYRAZ OLES ARE SYNTHESIZED FROM THE NEW 3-((1,3-DISUBSTITUTED5-PYRAZOLYL)THIO)PROPIONIC ACIDS DESCRIBED. THE NEW FUSED-RING COMPOUNDS HAVE EXCELLENT ANTI-INFLAMMATORY ACTIVITY; THEY RELIEVE EDEMAS AND ARE ALSO USEFUL AS ANTIPYRETICS AND ANALGESICS.

United States Patent 3 590 048 SUBSTITUTED THIOlYIiANO[2,3-c]PYRAZOLESLeo Ralph Swett and James Daniel Ratajczyk, Waul egan, 111., assignorsto Abbott Laboratories, North Chicago,

No Drawing. Filed Apr. 1, 1968, Ser. No. 717,813 Int. Cl. C07d 65/08 US.Cl. 260-310 4 Claims ABSTRACT OF THE DISCLOSURE 1,3-disubstituted 5,6dihydrothiopyrano[2,3-c] pyraz oles are synthesized from the new3-[(1,3-disubstituted- 5 pyrazolyl)thio]propionic acids described. Thenew fused-ring compounds have excellent anti-inflammatory activity; theyrelieve edemas and are also useful as antipyretics and analgesics.

The present invention is directed to compounds of the formula wherein ismethyl or phenyl, R is hydrogen or methyl, and Y is oxygen or The newcompounds are useful as antipyretics, analgesics andanti-inflammatories. The invention is also directed to the process ofmaking the compounds of the above formula and to the intermediates ofthe formula The new compounds exhibit anti-inflammatory and antipyreticactivity when administered to Warm-blooded animals at oral dosages of25-100 mg./kg.; at oral dosages above 100 mg./kg. the new compounds alsoshow analgesic effects and reduce capillary permeability. The compoundsof Formula I wherein Y is oxygen are generally more effective, i.e.,their effective dosage level is 3,590,048 Patented June 29, 1971 lowerthan that established for the compounds of Formula I wherein Y is Thenew compounds are particularly interesting as antiinflammatories andantipyretics because their therapeutic index is very high (the compoundsof Formula I have oral toxicities between 900 and 2,000 mg./kg.), andbecause they exhibit their activity at low oral dosages.

The following examples are given as illustrations for the preparationsof the new intermediates of Formula II and the anti-inflammatorycompounds of Formula I. However, these examples are not intended tolimit the invention in any respect. In all examples, the analyticalvalues are found to be in good agreement with the compounds of theassigned structure.

EXAMPLE 1 1,3-dimethyl-2-pyrazoline-5-thione To a stirred solution of112.1 g. of 1,3-dimethyl-2- pyrazolin-S-one in 1,500 ml. of refluxingxylene is added 87 g. of phosphorous pentasulfide. The resulting mixtureis stirred another 45 minutes under reflux and then allowed to settle.The hot xylene layer is decanted from the formed sludge and concentratedunder reduced pressure. The obtained residue from the xylene concentrateis crystallized from a minimum amount of hot isopropyl alco hol,resulting in 11.0 g. of pure 1,3-dimethyl-2-pyrazoline- S-thione,melting at 133.5134.5 C.

EXAMPLE 2 3-[ 1,3-dimethyl-5-pyrazolyl thio] propionic acid To asolution of 15.1 g. of sodium bicarbonate in 300 ml. of water is added20.5 g. of 1,3-dimethyl-2-pyrazoline- S-thione and the mixture is heatedwith stirring to C. A solution of 24.5 g. of 3-bromopropionic acid in300 ml. of Water containing 13.5 g. of sodium bicarbonate is then addedat once to the above hot mixture and stirring is continued at 70 C. forthree hours. Filtration of the hot solution removes a small amount ofinsoluble material. The filtrate is chilled and acidified with glacialacetic acid to give 26.7 g. (84% of theory) of pure 3-[(1,3-dimethyl-5-pyrazolyl)thio] propionic acid, melting at 127-128 C.

EXAMPLE 3 5,6-dihydro-1,3-dimethylthiopyrano[2,3-c]pyrazol- 4( 1H) -oneA mixture of 20 g. of 3-[(1,3-dimethyl-5-pyrazolyl) thio]-propionic acidand 250 g. of polyphosphoric acid is heated for one hour to C. andsubsequently poured onto crushed ice. The resulting clear solution isneutralized with a 50% aqueous sodium hydroxide solution While beingchilled in an ice bath. The crude ketone is crystallized from Water withcharcoal treatment to produce 12.9 g. (71% of theory) of pure, colorlessneedles of 5,6-dihydro 1,3 dimethylthiopyrano[2,3 c] pyrazol- 4(lH)-one,melting at l131l4 C.

EXAMPLE 4 1,4,5,6-te'trahydro-1,3-dimethylthiopyrano[2,3-c] pyrazol-4-olTo a suspension of 1.2 g. of lithium aluminum hydride in 250 ml. ofanhydrous ether is added, portionwise, 4.5 g. of5,6-dihydro-1,3-dimethylthiopyrano[2,3 c]pyrazol-4 (1H)-one and themixture is refluxed for 4 hours. Subsequently, the excess lithiumaluminum hydride is decomposed by the addition of 1.1 ml. of water, anda solution of 1.1 ml. of 15 aqueous sodium hydride and 3.3 ml. of wateris added before the mixture is filtered. The filtrate is evaporated todryness under reduced pressure and the residue is crystallized bydissolving it in the minimum amount of benzene and inducingcrystallization by the addition of hexane to give 3.7 g. of1,4,5,6-tetrahydro- 1,3-dimethylthiopyrano[2,3 c]pyrazol 4 ol, meltingat 95-96 C.

EXAMPLE 3- 1,3-dimethyl-5-pyrazolyl thio] butyric acid Following theprocedure of Example 2 but replacing the 3-bromopropionic acid usedthere with an equivalent amount of 3-bromobutyric acid produces3-[(1,3-dimethyl-5-pyrazolyl)thio]butyric acid. The pure material isobtained in a yield of 61% of theory as a yellow oil boiling at 160-180C. under 1-4 mm. pressure.

EXAMPLE 6 5,6-dihydro-1,3,6-trimethylthiopyrano-[2,3-c]pyrazo1-4-(1H)-one By following the procedure of Example 3 withthe compound of Example 5,5,6-dihydro-1,3,6-trimethylthiopyrano[2,3-c]pyrazol-4(1H)-one isobtained in a yield of 53.3% of theory after crystallizing the crudeproduct from water. The pure compound melts at 101.5-102.5 C.

EXAMPLE 7 1,4,5,6-tetrahydro-1,3,6-trimethylthiopyrano- [2,3-0]pyrazol-4-ol By reducing 6.9 g. of the compound of Example 6 by themethod of Example 4 using 1.5 g. of lithium aluminum hydride, a mixtureof the cis and trans isomers of 1,4,5,6 tetrahydro 1,3,6trimethylthiopyrano[2,3-c] pyrazol-4-ol is obtained in a yield of 2.4 g.The mixture has an indefinite melting point but analysis and theinfrared spectrum confirm the structure of the desired compound.

EXAMPLE :8

3 (3-methyl-1-phenyl-5-pyrazolyl)thio]propionic acid3-methyl-l-phenyl-2-pyrazoline-S-thione is made from3-methyl-1-phenyl-2-pyrazolin-5-one and phosphorous pentasulfide inaccordance with the process of Example 1. The pure compound,crystallized from ethanol, melts at 110-112 C.

By following the procedures of Example 2 using 35.7 g. of the abovethione and 29.0 g. of 3-bromopropionic acid, 3[(3-methy1-l-phenyl-S-pyrazolyl)thio]propionic acid is obtained in ayield of 38.4 g. after crystallizing the crude material fromethylacetate/hexane; it melts at 105- 107 C.

EXAMPLE 9 5,6-dihydro-3-methyl-l-phenylthiopyrano-[2,3-c]pyrazol-4(1H)-one Following the procedure of Example 3 with 92.0g. of the material of Example 8 and 1,565 g. of polyphosphoric acid,crude 5,6-dihydro-3-methyl-l-phenylthiopyrano[2,3-c]pyrazol-4( 1H)-oneis obtained which, after crystallization from aqueous ethanol, weighs74.0 g.; it melts at 124.5-126.5 C.

EXAMPLE 1'0 1,4,5,6-tetrahydro-3-methyl-l-phenylthiopyrano [2,3-c]pyrazol-4-o1 The compound of Example 9 is reduced in accordance with theprocedure of Example 4 to produce1,4,5,6-tetrahydro-3-methyll-phenylthiopyrano [2,3-0] pyrazol-4-ol in ayield of 83% of theory after crystallizing the crude material frombenzene/ hexane. The pure material melts at 144-145 C.

4 EXAMPLE 11 The anti-edema effect of the above compounds is establishedby the following procedure: edema is produced in the paws of rats by theinjection of carrageenan according to the method described by Winter etal. (Proc., Soc., Exp. Biol.,' Med., 1962, volume 111, page 544). Thetest compounds are administered orally at various dosages (6 rats perdosage) 30 minutes prior to the administration of the edema-producingcarrageenan. Edema is expressed as percent increase over normal pawsize; edema inhibition is calculated from the difference betweentheaverage edema size of the control group and the average edema size ofthe test group. The ED (i.e., the dose required to produce 25% edemasize reduction) is determined froma dosage/effect curve drawn onlogarithmic graph paper. In this manner, the ED of the compound ofExample '6 is established to be 49 mg./kg. orally; the ED of thecompound of Example 3 is determined to be 60 mg./kg. orally. With thecompounds of Example 4, 15% edema size reduction is found at mg./kg.orally.

EXAMPLE 12 The antipyretic activity of the compounds described above isestablished in the following manner: fever is produced in rats byintramuscular injections of an aqueous suspension of brewers yeast.After fever has stabilized, the test compounds are administered orally.Rectal temperatures are taken 1, 2 and 3 hours after drugadministration. The 3-hour reading is used to calculate fever andpercent reduction between the test group and a control group of animals,each group comprising 4-6 rats per group.

The ED (50% reduction of fever) for the compound of Example 6 is foundto be at 50 mg./kg. orally; with the compound of Example 3, a 15%reduction of fever is found at 50 mg./kg. orally.

EXAMPLE 13 Analgesic and reduction of capillary permeability producedwith the compounds of the present invention is established by amodification of the method described by Whittle (Brit. J. Pharm., 1964,volume 22, page 246): Mice are pre-treated with the test compound or aplacebo by oral administration thereof. I wenty minutes later, the miceare injected intravenously with 1-00 mg./ kg. of a 1% Evans Bluesolution in isotonic saline followed in 10 minutes by an intraperitonealinjection of 0.4 ml. of 0.5% aqueous acetic acid. Writhing produced bythe acid is counted for a period of 20 minutes. Analgesic efiect is thepercent inhibition of writhes calculated from the difference between thecontrol group and the test groups. Inhibition of permeability iscalculated as the percent inhibition of dye leakage into the peritonealcavity. Each group of test and control animals comprises 5 mice.

The analgesic ED for the compound of Example 6, established in thismanner, is mg./kg. orally and the ED' for capillary permeability(calculated dose which inhibits 50% dye leakage) is found to be at 220-mg./kg. orally; the analgesic ED of the compound of Example 3 is mg./kg.orally and the capillary permeability is found to be mg./ kg. orally.

The process of making the compounds of Formula I from the newintermediates of Formula 11 requires no solvent and is simply carriedout by treating the intermediate with an at least about 10-fold excessby weight of polyphosphoric acid. Excellent results are obtained byusing a 10- to 12-fold excess of polyphosphoric acid based on the weightof the intermediate but no undue effect is apparent if a 20-fold excessof polyphosphoric acid is used. The two reactants are heated for atleast 30 minutes to a temperature of between 1 00 and 160 C. Heatingbeyond three hours serves no beneficial purpose and temperatures above160 C. should be avoided in order to reduce possible by-productformation.

3,590,048 5 6 We claim: 4. The compound of claim 1 wherein R and Rboth 1. A compound of the formula are methyl and Y is oxygen.

ll References Cited Cm- 5 Biilow et al., Chem. Abst., vol. 12, p. 2562(1918).

U Eistert et al., Liebigs Ann. Chemie vol. 666, pp. 97-99 R and 105relied on (1963).

f S Fauran eta1., Chem. Abst. vol. 60 column 8013 (1964). R Patterson etal., The Ring 'Index, 2nd ed., pp. 158-9, wherein R is methyl or phenyl,R is hydrogen or methyl, 10 Wahmgtm Amer- Chem- 1960- and Y is oxygen or(lgegler et al., Chem. Abst. vol. 57, columns 725961 H NATALIE TROUSOF,Primary Examiner 15 2. The compound of claim 1 wherein R is phenyl, RUS. Cl. X.R. is hydrogen and Y is oxygen. 424-273 3. The compound ofclaim 1 wherein R is methyl, R is hydrogen and Y is oxygen.

